1. Field of the Invention
This invention relates to a series of novel non-peptidic quinolone carboxamides which exhibit selective inhibition of Calpain I, to compositions containing the novel non-peptidic quinolone carboxamides and methods for therapeutic use. The Calpain I inhibitors described in this invention possess particular utility in treatment of neurodegenerative diseases.
2. Reported Developments
Calpain is a cytosolic protease enzyme found in all mammalian tissue and cell types. There are two forms of the enzyme with different sensitivities to calcium; the high-sensitivity form, calpain I, is activated by a low calcium concentration (2-75 .mu.M), and the low-sensitivity form, calpain II, is activated by a higher calcium concentration (200-800 .mu.M). Although calpain II is the prominant form, calpain I is concentrated in synapses and neuronal cell bodies and is thought to be involved in the phenomenon of long-term synaptic potentiation.
The location of active calpain explain how calpain can promote: (1) down-regulation of membrane-associated active protein kinase C; (2) formation of a calpain-activated soluble kinase; and (3) reorganization of the cytoskeleton (Melloni, E., and Pontremoli, S. (1989), The Calpains, Trends Neurosci. 12, 438-44). Inactivation of the kinase results in repression of superoxide anion production, a process correlated to the protein kinase C-mediated phosphorylation of membrane proteins. Formation of a soluble, fully active kinase, operating in association with active calpain, results in selective modification in the organization of the cytoskeletal proteins, which is correlated with the extracellular discharge of granule contents. These conclusions have been reached by specific and direct inhibition of the proteinases, which results in: (1) a significant increase in superoxide anion production; (2) a marked decrease in the down-regulation of protein kinase C activity; (3) reduced formation of calpain-activated protein kinase; (4) decreased phosphorylation and phosphorylation-mediated proteolytic degradation of cytoskeletal proteins; and (5) inhibition of granule exocytosis.
In addition, studies of (Lee, K. S., Frank, S., Vanderklish, P., Arai, A., and Lynch, G. (1991), Inhibition of Proteolysis Protects Hippocampal Neurons from Ischemia, Proc. Nat. Acad. Sci. USA, 88, 7233) suggest that the inhibition of calpain may protect from various ischemia induced-neurodegeneration, essential hypertension, and benefits CNS disorders, and stroke.
A wide variety of peptide analogs are reported to inhibit the action of proteases (Mehdi, Shujaath, Cell-Penetrating Inhibitors of Calpain, TIPS, 16, 150 April 1991). These peptidyl analogs include: epoxisuccinates (E-64), leupeptin (CH.sub.3 CO-Leu-Leu-ArgH),and ketopeptides. However, these inhibitors suffer from some of the following disadvantages:
weak enzyme specificity, PA1 lack of inhibitory potency, PA1 inhibit wide variety of proteases in addition to calpain I, and PA1 multi-inhibition of various enzymes limits their therapeutic applicability.
A limited number of peptidyl methyl ketone analogs constitute a well-known class of compounds having enzymatic (papain, cathepsin B) inhibition activity. These analogs, however, are essentially devoid of potency and selectivity in inhibiting calpain I.
In spite of various known calpain inhibitors, no effective therapy has yet been developed for the majority of ischemia-induced neurodegenerative diseases, CNS disorders, and stroke. Consequently, there is a need for therapeutic agents effective in the treatment and prevention of these diseases.